Is Tobacco Use Associated With Risk of Recurrence and Mortality Among People With TB?

Background Associations between tobacco use and poor TB treatment outcomes are well documented. However, for important outcomes such as TB recurrence or relapse and mortality during treatment, as well as for associations with smokeless tobacco (ST), the evidence is not summarized systematically. Research Question Is tobacco use associated with risk of poor treatment outcomes among people with TB? Study Design and Methods The MEDLINE, Embase, and Cumulative Index of Nursing and Allied Health Literature databases were searched on November 22, 2021. Epidemiologic studies reporting associations between tobacco use and at least one TB treatment outcome were eligible. Independent double-screening, extractions, and quality assessments were undertaken. Random effects meta-analyses were conducted for the two primary review outcomes (TB recurrence or relapse and mortality during treatment), and heterogeneity was explored using subgroups. Other outcomes were synthesized narratively. Results Our searches identified 1,249 records, of which 28 were included in the meta-analyses. Based on 15 studies, higher risk of TB recurrence or relapse was found with ever using tobacco vs never using tobacco (risk ratio [RR], 1.78; 95% CI, 1.31-2.43; I2 = 85%), current tobacco use vs no tobacco use (RR, 1.95; 95% CI, 1.59-2.40; I2 = 72%), and former tobacco use vs never using tobacco (RR, 1.84; 95% CI, 1.21-2.80; I2 = 4%); heterogeneity arose from differences in study quality, design, and participant characteristics. Thirty-eight studies were identified for mortality, of which 13 reported mortality during treatment. Ever tobacco use (RR, 1.55; 95% CI, 1.32-1.81; I2 = 0%) and current tobacco use (RR, 1.51; 95% CI, 1.09-2.10; I2 = 87%) significantly increased the likelihood of mortality during treatment among people with TB compared with never using tobacco and not currently using tobacco, respectively; heterogeneity was explained largely by differences in study design. Almost all studies in the meta-analyses scored high or moderate on quality assessments. Narrative synthesis showed that tobacco use was a risk factor for other unfavorable TB treatment outcomes, as previously documented. Evidence on ST was limited, but identified studies suggested an increased risk for poor outcomes with its use compared with not using it. Interpretation Tobacco use significantly increases the risk of TB recurrence or relapse and mortality during treatment among people with TB, highlighting the need to address tobacco use to improve TB outcomes. Trial Registry PROSPERO; No.: CRD42017060821; URL: https://www.crd.york.ac.uk/prospero/

Tobacco use and TB contribute significantly to the global burden of disease, both individually and by acting synergistically.Although global tobacco use prevalence has declined (22.7% in 2007 to 19.6% in 2019), the total number of people using tobacco remains high because of population growth. 1 More than 80% of the 1.3 billion individuals worldwide who use tobacco live in low-income and middle-income countries (LMICs), where the TB burden also is substantial. 2Not only is this dual burden a grave problem in LMICs, but also tobacco use rates are estimated to be higher (approximately 8%) among people with TB than in the general population. 3ssuming that the relative prevalence of tobacco use and TB remain stable, it is estimated that > 40 million TB-related deaths will be attributable to tobacco use by 2050. 4 In addition, smokeless tobacco (ST) is consumed by > 300 million people worldwide, with some studies suggesting adverse associations with TB. 5,6 In South Asian countries, ST use tends to be even higher than tobacco use alone among people with TB. 7 TB is one of the most common chronic infectious diseases.In 2020, approximately 1.3 million TB-related deaths occurred among people without HIV, up from 1.2 million in 2019. 8COVID-19 has impeded further an already fragile global response to ending TB, with the first year-on-year estimated increase since 2005 in the number of TB deaths for 2020 and 2021. 8,9In these challenging times, integrating policies for tobacco control within routine TB care becomes particularly critical.
1][12] Although one of those reviews also reported significant association of retreatment TB with tobacco use, 12 this finding was based on only two studies.Since then, several studies have been published on this topic.Two systematic reviews in 2020 further identified negative impacts of tobacco use on TB treatment. 13,14However, these reviews presented combined outcomes, one as "poor outcomes" (combining failure, loss to follow-up, and death) 13 and the other as "unfavourable outcomes" (combining failure, transfer, loss to follow-up, and death). 14Both reviews did not include TB recurrence or relapse explicitly, and the latter included only current tobacco use, which limited the scope.
Given the importance of reducing TB recurrence or relapse especially in the context of drug resistance and related mortality to the End Tuberculosis Take-home Points Study Question: Is tobacco use associated with the risk of recurrence and mortality among people with TB? Results: A higher risk of TB recurrence or relapse was found with ever using tobacco vs never using tobacco (risk ratio [RR], 1.78; 95% CI, 1.31-2.43;I 2 ¼ 85%), current tobacco use vs no tobacco use (RR, 1.95; 95% CI, 1.59-2.40;I 2 ¼ 72%), and former tobacco use vs never using tobacco (RR, 1.84; 95% CI, 1.21-2.80;I 2 ¼ 4%).Moreover, ever tobacco use (RR, 1.55; 95% CI, 1.32-1.81;I 2 ¼ 0%) and current tobacco use (RR, 1.51; 95% CI, 1.09-2.10;I 2 ¼ 87%) significantly increased the likelihood of mortality among people with TB compared with never and no tobacco use, respectively.Evidence on smokeless tobacco was limited, but some studies suggested an increased risk of poor outcomes associated with its use compared with not using it.Interpretation: Tobacco use significantly increases the risk of TB recurrence or relapse and mortality during treatment among people with TB, highlighting the need to address tobacco use to improve TB outcomes.
Strategy, 15 we determined their association with tobacco use.Our risk estimates offer what was missed in previous meta-analyses, including an expanded remit to include all tobacco products.

Study Design and Methods
This review was registered with PROSPERO (Identifier: CRD42017060821) and follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (e-Appendix 1). 16arch Strategy and Selection Criteria Three electronic databases (MEDLINE, Embase, and Cumulative Index of Nursing and Allied Health Literature) were searched from inception to November 22, 2021.Search terms for tobacco use (smoking, smokeless) were developed from previous reviews, whereas those for TB outcomes were developed from a monograph on TB and tobacco control. 17Searches were conducted by combining both sets of terms (e-Appendix 2); no language restrictions were applied during searching.
We included epidemiologic studies (cohort, case control, and crosssectional) on people with TB (not restricted by age, sex, comorbidities, pulmonary or extrapulmonary presentation, or geographic region) that measured the effect of ever, current, or past tobacco use (with smoke and smokeless) on TB treatment outcomes (Table 1).Studies that included both people with drugsusceptible and drug-resistant TB (DRTB) were eligible and were analyzed as explained herein.However, studies on treatment outcomes exclusively among people with DRTB were excluded because the treatment course and its association with tobacco is likely to be different in this population.Similarly, studies on treatment outcomes exclusively among people with retreatment TB were excluded, whereas studies that included both people with new and retreatment TB were eligible.Our primary review outcomes were TB recurrence or relapse and mortality during treatment; within the outcome of mortality, we also included all-cause mortality among people with TB and TB mortality.Secondary outcomes were default, failure, unsuccessful treatment (combined mortality, default, and failure), delayed sputum conversion, treatment nonadherence, severity of disease, and drug resistance development.Studies reporting secondhand tobacco smoke exposure or unclear outcomes were excluded.Randomized controlled trials, reviews, case series, and case reports also were excluded.
We screened the references of included articles and relevant systematic reviews to identify additional studies.All identified reports underwent deduplication and independent double screening by two of the authors (A.R. and M. B.) based on title and abstract.Full-text review of potentially relevant articles also was assessed independently by two reviewers (F. S. and M. B.), whereas a third reviewer (A.L. V. or O. D.) was consulted when consensus could not be reached.During screening, we considered only studies written in English because of constrained resources for translation.

Data Extraction and Synthesis
Groups of two reviewers (A.R. and A.-M. M. or A. J. and A. L. V.) independently extracted data from included studies using a piloted data extraction form specifically designed for this review.The main sections included: study design and characteristics; sample size and  Delayed conversion rate of positive sputum smear results in patients with pulmonary TB at follow-up (after 2 months of therapy).Nonconversion was defined as persistent positive sputum smear results for patients with TB at the end of the 2-or 3-mo intensive phase of treatment.

Poor treatment adherence
Both compliance with the number of days anti-TB drugs were taken or the number of tablets taken of the prescribed amount is considered an acceptable measure of adherence.

Severity of disease b
Higher bacillary load (smear grading 3þ and higher), more cavitation (advanced radiologic lesions), hospitalized, symptoms (cough, dyspnea, upper zone involvement) Drug-resistant TB a TB that is resistant to $ 1 first-line antituberculosis drugs a World Health Organization Global Tuberculosis Report, 2013. 18b TB/tobacco monograph. 17articipant demographics; and exposure and outcome details, including type of tobacco (with smoke or smokeless), type of exposure (ever, current, or past), frequency of outcome among exposed and unexposed participants, and the measures of effect reported.The extraction forms were compared, and disagreements were resolved in the first instance by discussion or with a third reviewer (O.D.) if consensus could not be reached.
Risk of bias was evaluated using the Quality Assessment Tool for Quantitative Studies, 19 and each study was rated as strong, moderate, or weak in the following categories: study design, analysis, withdrawals and dropouts, data collection, selection bias, and confounders.Based on these, an overall rating was provided.Subsequently, we considered the influence of studies with weak methodologic quality on summary effect sizes.
Meta-analysis was carried out using RevMan version 5.4 software (Cochrane Collaboration). 20We classified the studies according to tobacco type (with smoke or smokeless) and exposure type (ever vs never use or current use vs current nonuse or past use vs never use) for each treatment outcome and performed meta-analysis for groups that included two or more studies.We limited the meta-analysis to our two primary outcomes (TB recurrence or relapse and mortality during treatment) and narratively synthesized the additional outcomes because they largely were covered in two reviews published in 2020. 13,14r the meta-analyses, we used the number of individuals exposed, number of individuals unexposed, and events observed in both those groups as reported in the individual studies to calculate risk ratios (RRs) and 95% CIs.These estimates were pooled using random effects models and are presented as forest plots.Heterogeneity of included studies was assessed using the I 2 statistic, and the reasons for heterogeneity were explored through subgroup analyses according to study design, quality, and presence of comorbidities among participants.In addition, sensitivity analyses were performed by removing (1) studies that included people with DRTB and (2) studies that included people with retreatment TB.Finally, the presence of publication bias was assessed based on funnel plots, and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessments were used to rate the certainty of evidence for the primary outcomes. 21We did not explore the doseresponse effect of duration and amount of tobacco use on TB outcomes.

Results
Our       reported in two publications each. 24,25,62,63,82,83,123,124or the two primary outcomes, we included 36 studies (20 on recurrence or relapse 36,39,43,47,51,64,67,71,84,88,94,96,97,100,109,112,118,123,127,147 and 16 on mortality during treatment. 32,54,55,57,66,70,74,90,95,99,103,111,120,125,126,135owever, data from eight studies could not be pooled (five on recurrence or relapse 39,47,67,123,127 and three on mortality 55,66,90 ) because the numbers required for computing RRs were not reported.Therefore, 15 studies were included in the TB recurrence or relapse meta-analyses and 13 studies were included in the mortality during treatment meta-analyses (e-Table 1).1).The overall rating on the risk-of-bias assessments was strong for 68 studies, moderate for 41 studies, and weak for five studies (e-Table 2).Risk of bias was not assessed for the remaining nine studies because we could not extract any results from them.

TB Recurrence or Relapse
Fifteen studies provided the necessary data to be pooled in at least one of the three meta-analyses: five for ever using tobacco, 94,96,100,109,147 13 for current tobacco use, 36,43,51,64,71,84,88,94,96,97,112,118,147 and three for former tobacco use 94,96,147 (some studies reported on more than one exposure).No studies on ST use were found.
Compared with never or no tobacco use, the risk of TB recurrence or relapse was found to be higher with ever tobacco use (pooled RR, ).All three associations were statistically significant and showed a high degree of heterogeneity (Fig 2A -C).Subgroup analyses showed that variations in study design, quality, and presence of comorbidities could explain some of the heterogeneity, although substantial unexplained heterogeneity within each of these subgroups remained (Table 3); removing the studies that included people with DRTB and retreatment TB did not change the overall findings (e-Fig 1A-M).Funnel plots appeared generally symmetrical, suggesting minimal publication bias (e-Fig 2A-C).The GRADE assessments for all three meta-analyses were very low (e-Fig 3A-C).

Mortality During TB Treatment
Of the 13 studies, four provided estimates for ever using tobacco vs never using tobacco, 57,111,126,135 and nine provided estimates for current tobacco use vs no tobacco use 32,46,54,70,74,99,103,120,125 Only the current tobacco use analysis showed a high degree of heterogeneity, which largely was explained by differences in study design (Table 3).Like recurrence or relapse, removing the studies that included people with DRTB and retreatment TB did not change the overall findings (e-Fig 4A-G).Some funnel plot asymmetry was observed (e-Fig 5A , 5B), and the GRADE assessment was low for both meta-analyses (e-Fig 6A -6B).

Secondary Outcomes
In addition to mortality during treatment, we included 11 studies on all-cause mortality among people with TB 37,42,58,67,68,94,95,105,123,140,144 and 11 on TB mortality. 22,23,27,30,35,44,47,48,75,115,121  chestjournal.orgmortality, except for two studies that did not provide risk estimates 58,67 and two studies that found no association with current tobacco use, 94,105 the remaining study reported increased risk with tobacco use compared with no tobacco use.For TB mortality, all studies reported increased risk with tobacco use and one study report increased risk with ST use in addition (e-Table 3). 35134,135 Except for one study, 62 all others reported increased risk with tobacco use compared with never or no tobacco use.Regarding treatment failure, nine of 12 identified studies provided risk estimates, all reporting increased risk with tobacco use. 26,42,52,57,62,74,82,93,119,123,126,138Of these, the risk could not be extracted from four studies, 24,49,61,137 whereas most of the remaining ones reported increased risk, including three studies that included the use of ST products. 91,104,122 association between tobacco use and delayed sputum conversion was reported in 25 studies, 24,31,38,40,52,53,66,69,72,81,86,89,92,94,101,106,110,114,126,130,132,139,141,142,148 and all but one study 40 found increased risks.For treatment nonadherence, effect measures were extracted from seven of eight included studies, 33,77,82,113,116,133,135,136 all reporting increased risk associated with tobacco use, and one also reporting increased risk associated with ST use. 77Disease severity was indicated by risk of hospitalization or cavitation in five included studies, 32,126,128,130,143 and all reported increased risk with tobacco use.Finally, one case-control study reported an increased risk of drug resistance developing with tobacco use compared with no tobacco use. 131

Discussion
This systematic review identified a substantial number of epidemiologic studies on the association between tobacco use and TB treatment outcomes, and the synthesis clearly showed an increased risk with tobacco use.For the primary outcomes, tobacco use significantly increased the risk of TB recurrence or relapse and mortality during treatment.To our knowledge, the link between tobacco use and TB recurrence or relapse has not been reviewed systematically since 2007, 12 and no meta-analysis has been conducted until now, although the need for it has been highlighted. 149,150For mortality, previous reviews largely identified TB mortality estimates, [10][11][12] which identified the association between tobacco use and TB  occurrence, rather than treatment outcomes.A 2010 publication summarized the three 2007 reviews and found them to be consistent on TB mortality, 151 as did the 2014 US Surgeon General's report. 152Although we included the TB mortality studies and reached similar conclusions, our meta-analysis focused on mortality during treatment, because this provided a more objective indication of mortality as a treatment outcome.
Our review also found increased risks for default, failure, nonadherence, and delayed sputum conversion.Most of these outcomes were covered in two recent metaanalyses, 13,14 both reporting adverse associations with tobacco use.Although our updated searches identified newer studies, we predicted that further meta-analyses would not change the results.Disease severity and development of DRTB were two additional outcomes we included.However, no meta-analyses were conducted because the definition of severity varied across studies, although only one study reported on development of DRTB.Nonetheless, increased risk with tobacco use was found for risk of hospitalization, risk of cavitation, and risk of drug resistance developing.
To our knowledge, the association between ST and TB treatment outcomes has not been reviewed previously.We found eight studies covering unsuccessful treatment, TB mortality, and nonadherence, but the ST-related risks were reported only in six studies.Nonetheless, all but one study found increased risks associated with ST use.Although links between nasal ST (eg, snuff) and increased susceptibility to pulmonary infections have been discussed through mechanisms like decreased mucociliary clearance 153 and altered microbiome, 154 further research to elucidate our findings with other ST products are needed.Similarly, among the tobacco use studies, only a few specified bidi and other noncigarette forms, whereas none reported separate effect measures associated with their use.
The key strengths of this review are its rigorous methodologies, the high quality of included studies, and the use of GRADE for the primary outcomes.The limitations, nonetheless, are as follows.First, because the primary studies presented varied estimates (eg, ORs, hazard ratios, and so forth), we used their numbers to calculate RRs for pooling.This meant that studies that did not report the necessary numbers were left out of the meta-analyses.However, these were few and largely reported increased risks with tobacco use.Only two studies on mortality during treatment reported hazard ratios of < 1.00, but one article did not describe the study in adequate detail, 55 whereas the effect was not statistically significant in the second study. 66Our analytical strategy also meant that the effect of important confounders such as age, alcohol, and so forth were not accounted for adequately.The way data were reported on covariates did not allow for their use in metaregression, as originally planned.However, where available within primary studies, we reported adjusted estimates (e-Table 3).Also, when assessing quality, we considered the extent to which studies adjusted for potential confounders.
Another limitation of the meta-analyses is the high heterogeneity: only the ever using tobacco and mortality during treatment analysis showed no heterogeneity.Further, we included studies with combined drugsusceptible TB and DRTB, as well as new and retreatment TB samples.However, we did our best to explain our findings using subgroup and sensitivity analyses.We found that differences in study design, quality, and participant characteristics explained some of the heterogeneity and that removing the studies that included people with DRTB and retreatment TB did not change the overall findings.Additional sources of heterogeneity likely included the geographical spread of studies and the different tobacco products used, but not enough information was available for further exploration.We noted some funnel plot asymmetry in the mortality analyses, suggesting the possibility of publication bias.However, this also may be the result of heterogeneity and chance 155 and was not assessed further.We also could not rule out the possibility of bias from five studies that were excluded because of language restrictions.Finally, the GRADE assessments for all meta-analyses were either very low or low, suggesting that the true effect may differ from our estimates.However, we believe this was explained largely by the observational study designs and the lack of doseresponse effects in most included studies.

Interpretation
Taken together, our findings show increased risk of TB recurrence or relapse and mortality during treatment with tobacco use compared with never or no tobacco use.Tobacco use is also a clear risk factor for other unfavorable TB treatment outcomes, as documented in earlier reviews.Although evidence is limited on ST, it still suggests that we need to be cognizant of the risks associated with its use, especially given its disproportionately high prevalence in LMICs. 156The integration of tobacco cessation within TB services offers a viable option, particularly in LMICs. 12A large proportion of people with TB who use tobacco are willing to stop, and those who stop tobacco use have better treatment success (91% vs 80%; P < .001)and lower relapse rates (6% vs 14%; P < .001). 157The results of our review provide additional evidence to invest in these policies and practices to reduce the global TB and tobacco-related disease burden.

Funding/Support
The authors have reported to CHEST that no funding was received for this study.
for TB who were declared cured or who completed treatment at the end of the most recent course and again receive a diagnosis of an episode of TB (either a true relapse or a new episode of TB caused by reinfection, also known as recurrence).Mortality b TB mortality: the cause of death designated as being the result of TB or dying with verified TB.Death certificate notification, medical records, or family interviews are considered acceptable sources of information.Death during TB treatment All-cause mortality among people with a TB diagnosis Treatment default a Those previously treated for TB who were declared lost to follow-up at the end of the most recent course of treatment Treatment failure a Those treated for TB for whom the most recent course of treatment failed Delayed sputum conversion a

Figure 2 -
Figure 2 -A, Forest plot showing risk of TB recurrence or relapse risk associated with ever using tobacco.B, Forest plot showing risk of TB recurrence or relapse risk associated with current tobacco use.C, Forest plot showing risk of TB recurrence or relapse risk associated with former tobacco use.

Figure 3 -
Figure 3 -A, Forest plot showing risk of mortality during treatment associated with ever using tobacco among people with TB.B, Forest plot showing risk of mortality during treatment associated with current tobacco use among people with TB.

TABLE 1 ]
Definitions for TB Treatment Outcomes

TABLE 2 ]
Summary of Included Studies

, 95% CI Study or Subgroup log[Risk Ratio] SE Weight Risk Ratio IV, Random, 95% CI
For all-cause